RANKL elevation activates the NIK/NF-κB pathway, inducing obesity in ovariectomized mice

in Journal of Endocrinology
Authors:
Kayo Mori Laboratory of Molecular and Cellular Biochemistry, Division of Oral Biological Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka, Japan
Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Kyushu University, Higashi-ku, Fukuoka, Japan

Search for other papers by Kayo Mori in
Current site
Google Scholar
PubMed Close
,
Akiko Mizokami Oral Health/Brain Health/Total Health Research Center, Kyushu University, Higashi-ku, Fukuoka, Japan

Search for other papers by Akiko Mizokami in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-7490-5190
,
Tomomi Sano Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka, Japan

Search for other papers by Tomomi Sano in
Current site
Google Scholar
PubMed Close
,
Satoru Mukai Department of Health and Nutrition Care, Faculty of Allied Health Sciences, University of East Asia, Shimonoseki, Japan

Search for other papers by Satoru Mukai in
Current site
Google Scholar
PubMed Close
,
Fumitaka Hiura Laboratory of Molecular and Cellular Biochemistry, Division of Oral Biological Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan

Search for other papers by Fumitaka Hiura in
Current site
Google Scholar
PubMed Close
,
Yasunori Ayukawa Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Kyushu University, Higashi-ku, Fukuoka, Japan

Search for other papers by Yasunori Ayukawa in
Current site
Google Scholar
PubMed Close
,
Kiyoshi Koyano Division of Advanced Dental Devices and Therapeutics, Faculty of Dental Science, Kyushu University, Fukuoka, Japan

Search for other papers by Kiyoshi Koyano in
Current site
Google Scholar
PubMed Close
,
Takashi Kanematsu Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka, Japan

Search for other papers by Takashi Kanematsu in
Current site
Google Scholar
PubMed Close
, and
Eijiro Jimi Laboratory of Molecular and Cellular Biochemistry, Division of Oral Biological Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
Oral Health/Brain Health/Total Health Research Center, Kyushu University, Higashi-ku, Fukuoka, Japan

Search for other papers by Eijiro Jimi in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0003-3616-5299

Correspondence should be addressed to A Mizokami or T Kanematsu or E Jimi: akiko-k@dent.kyushu-u.ac.jp or taka-kanematsu@dent.kyushu-u.ac.jp or ejimi@dent.kyushu-u.ac.jp
DOI:
https://doi.org/10.1530/JOE-21-0424
Volume/Issue:
Volume 254: Issue 1
Article Type:
Research Article
Page Range:
27–36
Online Publication Date:
31 May 2022
Copyright:
© Society for Endocrinology 2022
Restricted access
Rent on DeepDyve

Sign up for journal news

Menopausal women are susceptible to visceral obesity, which increases the risk of metabolic disorders. However, the mechanisms of menopause-induced visceral fat accumulation are not fully understood. Circulating levels of receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) are elevated in an animal model of menopause. RANKL, a multifunctional cytokine, activates the NF-κB pathway, which serves as a pivotal mediator of inflammatory responses. Here, we investigated whether RANKL-induced non-canonical NF-κB pathway activation induces inflammation and lipid accumulation in adipose tissues. RANKL induced Tnfa expression via the non-canonical NF-κB pathway in bone marrow cells. We therefore analyzed aly/aly mice, in which the non-canonical NF-κB pathway is not activated, owing to an inactive form of NF-κB-inducing kinase. A postmenopausal obesity model was generated by ovariectomy and subsequent high-fat and high-sucrose diet feeding. In aly/aly mice with postmenopausal obesity, serum RANKL levels were elevated, and hepatic lipid accumulation and adipocyte hypertrophy were suppressed, resulting in reduced macrophage infiltration and inflammatory cytokine mRNA expression in visceral adipose tissue. Furthermore, aly/aly mice showed protection from glucose intolerance and insulin resistance, which were observed in ovariectomized WT obese mice. These findings indicate that non-canonical NF-κB pathway activation via serum RANKL elevation contributes to postmenopausal obesity.

Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 704 121 0
PDF Downloads 292 60 0

 

  • Collapse
  • Expand
Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© Society for Endocrinology 2022
Page(s):
10
Article Type:
Research Article
Received Date:
30 Mar 2022
Accepted Date:
12 Apr 2022
Print Publication Date:
01 Jul 2022
Online Publication Date:
31 May 2022
Keywords:
NF-κB-inducing kinase; menopause; obesity; metabolic disorder

  • Azizieh FY, Shehab D, Jarallah KAl, Gupta R & Raghupathy R 2019 Circulatory levels of RANKL, OPG, and oxidative stress markers in postmenopausal women with normal or low bone mineral density. Biomarker Insights 14 1177271919843825. (https://doi.org/10.1177/1177271919843825)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Barros RPA & Gustafsson JÅ 2011 Estrogen receptors and the metabolic network. Cell Metabolism 14 289–299. (https://doi.org/10.1016/j.cmet.2011.08.005)

  • Barros RPA, Gabbi C, Morani A, Warner M & Gustafsson JA 2009 Participation of Erα and Erβ in glucose homeostasis in skeletal muscle and white adipose tissue. American Journal of Physiology, Endocrinology and Metabolism 297 E124–E133. (https://doi.org/10.1152/ajpendo.00189.2009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bierhaus A & Nawroth PP 2009 Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications. Diabetologia 52 2251–2263. (https://doi.org/10.1007/s00125-009-1458-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bord S, Ireland DC, Beavan SR & Compston JE 2003 The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts. Bone 32 136–141. (https://doi.org/10.1016/s8756-3282(0200953-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Boutens L & Stienstra R 2016 Adipose tissue macrophages: going off track during obesity. Diabetologia 59 879–894. (https://doi.org/10.1007/s00125-016-3904-9)

  • Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM & Chabo C et al.2007 Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56 1761–1772. (https://doi.org/10.2337/db06-1491)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Catrysse L & van Loo G 2017 Inflammation and the metabolic syndrome: the tissue-specific functions of NF-κB. Trends in Cell Biology 27 417–429. (https://doi.org/10.1016/j.tcb.2017.01.006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Craft CS, Broekelmann TJ, Zou W, Chappel JC, Teitelbaum SL & Mecham RP 2012 Oophorectomy-induced bone loss is attenuated in MAGP1-deficient mice. Journal of Cellular Biochemistry 113 93–99. (https://doi.org/10.1002/jcb.23331)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME & Maliszewski CR et al.1999 RANK is essential for osteoclast and lymph node development. Genes and Development 13 2412–2424. (https://doi.org/10.1101/gad.13.18.2412)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL & Riggs BL 2003 Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. Journal of Clinical Investigation 111 1221–1230. (https://doi.org/10.1172/JCI17215)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Foryst-Ludwig A & Kintscher U 2010 Metabolic impact of estrogen signalling through ERalpha and ERbeta. Journal of Steroid Biochemistry and Molecular Biology 122 74–81. (https://doi.org/10.1016/j.jsbmb.2010.06.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ghisletti S, Meda C, Maggi A & Vegeto E 2005 17β-Estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. Molecular and Cellular Biology 25 2957–2968. (https://doi.org/10.1128/MCB.25.8.2957-2968.2005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gorres BK, Bomhoff GL, Morris JK & Geiger PC 2011 In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake. Journal of Physiology 589 2041–2054. (https://doi.org/10.1113/jphysiol.2010.199018)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hanada R, Leibbrandt A, Hanada T, Kitaoka S, Furuyashiki T, Fujihara H, Trichereau J, Paolino M, Qadri F & Plehm R et al.2009 Central control of fever and female body temperature by RANKL/RANK. Nature 462 505–509. (https://doi.org/10.1038/nature08596)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hanada R, Hanada T, Sigl V, Schramek D & Penninger JM 2011 RANKL/RANK-beyond bones. J Mol Med (Berl)89 647–656. (https://doi.org/10.1007/s00109-011-0749-z.)

  • Harte AL, Varma MC, Tripathi G, McGee KC, Al-Daghri NM, Al-Attas OS, Sabico S, O’Hare JP, Ceriello A & Saravanan P et al.2012 High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. Diabetes Care 35 375–382. (https://doi.org/10.2337/dc11-1593)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC & Riggs BL 1999 Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140 4367–4370. (https://doi.org/10.1210/endo.140.9.7131)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Khosla S, Arrighi HM, Melton LJ III, Atkinson EJ, O’Fallon WM, Dunstan C & Riggs BL 2002 Correlates of osteoprotegerin levels in women and men. Osteoporosis International 13 394–399. (https://doi.org/10.1007/s001980200045)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kiechl S, Wittmann J, Giaccari A, Knoflach M, Willeit P, Bozec A, Moschen AR, Muscogiuri G, Sorice GP & Kireva T et al.2013 Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nature Medicine 19 358–363. (https://doi.org/10.1038/nm.3084)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G & Itie A et al.1999 OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397 315–323. (https://doi.org/10.1038/16852)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G & Scully S et al.1998 Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93 165–176. (https://doi.org/10.1016/s0092-8674(0081569-x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee NJ, Clarke IM, Enriquez RF, Nagy V, Penninger J, Baldock PA & Herzog H 2018 Central RANK signalling in NPY neurons alters bone mass in male mice. Neuropeptides 68 75–83. (https://doi.org/10.1016/j.npep.2018.02.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu JM, Zhao HY, Ning G, Zhao YJ, Chen Y, Zhang Zh, Sun LH, Xu MY & Chen JL 2005 Relationships between the changes of serum levels of OPG and RANKL with age, menopause, bone biochemical markers and bone mineral density in Chinese women aged 20–75. Calcified Tissue International 76 1–6. (https://doi.org/10.1007/s00223-004-0007-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu Y, Sheng L, Xiong Y, Shen H, Liu Y & Rui L 2017 Liver NF-κB-inducing kinase promotes liver steatosis and glucose counterregulation in male mice with obesity. Endocrinology 158 1207–1216. (https://doi.org/10.1210/en.2016-1582)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Malle EK, Zammit NW, Walters SN, Koay YC, Wu J, Tan BM, Villanueva JE, Brink R, Loudovaris T & Cantley J et al.2015 Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity. Journal of Experimental Medicine 212 1239–1254. (https://doi.org/10.1084/jem.20150218)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Miyawaki S, Nakamura Y, Suzuka H, Koba M, Yasumizu R, Ikehara S & Shibata Y 1994 A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. European Journal of Immunology 24 429–434. (https://doi.org/10.1002/eji.1830240224)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mizokami A, Wang D, Tanaka M, Gao J, Takeuchi H, Matsui T & Hirata M 2016 An extract from pork bones containing osteocalcin improves glucose metabolism in mice by oral administration. Bioscience, Biotechnology, and Biochemistry 80 2176–2183. (https://doi.org/10.1080/09168451.2016.1214530)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Murphy AJ, Guyre PM & Pioli PA 2010 Estradiol suppresses NF-κB activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. Journal of Immunology 184 5029–5037. (https://doi.org/10.4049/jimmunol.0903463)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ono T, Hayashi M, Sasaki F & Nakashima T 2020 RANKL biology: bone metabolism, the immune system, and beyond. Inflammation and Regeneration 40 2. (https://doi.org/10.1186/s41232-019-0111-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pussinen PJ, Havulinna AS, Lehto M, Sundvall J & Salomaa V 2011 Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 34 392–397. (https://doi.org/10.2337/dc10-1676)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Roepke TA 2009 Oestrogen modulates hypothalamic control of energy homeostasis through multiple mechanisms. Journal of Neuroendocrinology 21 141–150. (https://doi.org/10.1111/j.1365-2826.2008.01814.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rogers A, Saleh G, Hannon RA, Greenfield D & Eastell R 2002 Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 87 4470–4475. (https://doi.org/10.1210/jc.2002-020396)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shen H, Sheng L, Chen Z, Jiang L, Su H, Yin L, Omary MB & Rui L 2014 Mouse hepatocyte overexpression of NF-κB-inducing kinase (NIK) triggers fatal macrophage-dependent liver injury and fibrosis. Hepatology 60 2065–2076. (https://doi.org/10.1002/hep.27348)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sheng L, Zhou Y, Chen Z, Ren D, Cho KW, Jiang L, Shen H, Sasaki Y & Rui L 2012 NF-κB-inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action. Nature Medicine 18 943–949. (https://doi.org/10.1038/nm.2756)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H & Flier JS 2006 TLR4 links innate immunity and fatty acid-induced insulin resistance. Journal of Clinical Investigation 116 3015–3025. (https://doi.org/10.1172/JCI28898)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shoelson SE, Lee J & Goldfine AB 2006 Inflammation and insulin resistance. Journal of Clinical Investigation 116 1793–1801. (https://doi.org/10.1172/JCI29069)

  • Soysa NS, Alles N, Weih D, Lovas A, Hussain Mian A, Shimokawa H, Yasuda H, Weih F, Jimi E & Ohya K et al.2010 The pivotal role of the alternative NF-κB pathway in maintenance of basal bone homeostasis and osteoclastogenesis. Journal of Bone and Mineral Research 25 809–818. (https://doi.org/10.1359/jbmr.091030)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sun SC 2017 The non-canonical NF-κB pathway in immunity and inflammation. Nature Reviews: Immunology 17 545–558. (https://doi.org/10.1038/nri.2017.52)

  • Sun SC & Ley SC 2008 New insights into NF-κB regulation and function. Trends in Immunology 29 469–478. (https://doi.org/10.1016/j.it.2008.07.003)

  • Takakura N, Matsuda M, Khan M, Hiura F, Aoki K, Hirohashi Y, Mori K, Yasuda H, Hirata M & Kitamura C et al.2020 A novel inhibitor of NF-κB-inducing kinase prevents bone loss by inhibiting osteoclastic bone resorption in ovariectomized mice. Bone 135 115316. (https://doi.org/10.1016/j.bone.2020.115316)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wen B, Zhao L, Zhao H & Wang X 2018 Liraglutide exerts a bone-protective effect in ovariectomized rats with streptozotocin-induced diabetes by inhibiting osteoclastogenesis. Experimental and Therapeutic Medicine 15 5077–5083. (https://doi.org/10.3892/etm.2018.6043)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xiong J, Cawley K, Piemontese M, Fujiwara Y, Zhao H, Goellner JJ & O’Brien CA 2018 Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nature Communications 9 2909. (https://doi.org/10.1038/s41467-018-05244-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yu H, Lin L, Zhang Z, Zhang H & Hu H 2020 Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduction and Targeted Therapy 5 209. (https://doi.org/10.1038/s41392-020-00312-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu P, Zhang Z, Huang X, Liang S, Khandekar N, Song Z & Lin S 2018 RANKL reduces body weight and food intake via the modulation of hypothalamic NPY/CART expression. International Journal of Medical Sciences 15 969–977. (https://doi.org/10.7150/ijms.24373)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation